Epidermis undergoes continuous self-renewal through a tight balance of cell proliferation, differentiation and cell death. This balance is regulated by both epidermal cell-intrinsic processes and paracrine effects from dermal cells, including fibroblasts and lymphocytes. Among a complex array of signaling molecules and transcription factors, the IKK/NF-: B and JNK/AP-1 signaling cascades have been implicated as dominant regulators in mediating epidermal cell-intrinsic processes. NF-: B controls epidermal growth, while AP-1 induction via JNK is responsible for the epidermal hyperplasia and neoplasia associated with NF-: B blockade. However, there are functional diversities and even antagonisms among AP-1 subunits. Specifically, although both JunB and c-Jun are involved in mediating epidermal differentiation markers, JunB inhibits epidermal cell growth and induces cell senescence;whereas c-Jun promotes epidermal growth and neoplasia. Moreover, epidermal-specific deletion of JunB alone or along with c-Jun, but not c-Jun alone, in mice leads to an inflammatory skin phenotype with resemblance to human arthritic and psoriatic diseases. These findings underscore important roles for JunB and c-Jun in epidermal well-being and pathogenesis, and suggest that they are functionally antagonistic and redundant in mediating epidermal cell growth and differentiation, respectively. The first goal of this proposal is to determine the molecular mechanisms of Jun proteins in mediating epidermal cell-intrinsic processes. To do this, we will perform systemic structure-functional studies to define the functional specificity of JunB and c-Jun sub-domains in epidermal growth and differentiation. We will also determine the nature of the antagonism or synergism between JunB and c- Jun, and identify their downstream target genes by genome-wide gene expression analysis. The second goal is to determine how JunB and c-Jun contribute to epidermal tumorigenesis. To do this, we will use the recently established human squamous cell carcinoma models to examine gain- or loss-of-function effects of JunB and c-Jun, as well as their downstream target, p16, on epidermal tumor growth, maintenance and regression. This effort is based on the premise that characterizing the molecular mechanisms governing the functional specificity of JunB and c-Jun will provide new insights into both basic epithelial biology and better defined therapeutic targets. PUBLIC HEALTH RELEVANCE: Abnormalities of epidermal growth or differentiation account for many diseases affecting a large proportion of the U.S. population. Among these disorders are atopic dermatitis, psoriasis, squamous cell carcinoma, basal cell carcinoma and chronic wounds. The efforts of this proposal are designed to characterize the genetic regulatory mechanisms governing epidermal homeostasis and neoplastic pathogenesis, and therefore provide meaningful insights to better defined therapeutic targets for skin disorders as well as other types of diseases.